Process for preparing 3-nitrobenzaldehyde ethers



United States Patent 0 3,085,111 I PROCESS FOR PREPARING3-NITROBENZALDE- HYDE ETHERS Robert I. Meltzer, Rockaway, N..l'.,assignor to Warner- Lambert Pharmaceutical Company, Morris Plains, N.J.,a corporation of Delaware No Drawing. Original application Mar. 19,1957, Ser.

No. 646,971, now Patent No. 2,954,399, dated Sept.

27, 1960. Divided and this application Feb. 5, 1960,

Ser. No. 6,844

1 Claim. (Cl. ace-aw compounds show considerable promise for thetreatment of certain diseases which might have been successfully treatedwith thyroxine were it not that the patients are unable to tolerate thebasal metabolic rate elevation which thyroxine would produce.

It is known that 3,3-diiodothyronine may be obtained readily byiodination of 3-iodothyronine. It is further known that3,3,5-triiodothyronine may be obtained readily by iodination of3,3'-diiodothyronine and also directly by iodination of 3-iodothyronine.However, the prior art methods of preparing 3-iodothyronine are lengthy,impractical and give low overall yields.

It is an object of this invention to provide a new, convenient andpractical process for the preparation of certain important syntheticprecursors of S-iodothyronine as well as a process for the preparationof 3-iodothyronine itself. Another object of this invention is toprovide new and valuable compounds which may be used as intermediates inthe synthesis of 3-iodothyronine.

The present invention provides a novel approach to the synthesis of3-iodothyronine and certain precursors thereof in accordance with thefollowing scheme of reactions:

Cl- CHO 4-ch1oro-3-nitrobenzaldehyde l omo-Q-on 4-methoxyphcno1 I NHz III hlppuric acid 00 4-[4-(4methoxyl phenoxy) -3-nitrobcnz a1]- 0 2-phenyl-5-oxazolone OaHs lAlkaline hydrolysis methoxyphenoxy) -3- NO ENG-1 11 nitrocinnamic acid I Reduction a-Benzamido-3- amino-444-methoxyphenoxy) cinnamic acid ENG-OM15 Diazotization, treatmenk I! w hiodid a-Benzamido-3-iodo-4-(4-methoxyphenoxy) cinnarnic acid4-[3-iodo-4-(4-mcthoxyphenoxy) benzal] 2-phenyl-5- oxazolone P, HLH BrNHa 3-iodothyronine The condensation of 4-chloro-3-nitrobenzaldehydewith 4-methoxyphenol may be carried out in the presence of potassiumhydroxide and pyridine over the temperature range 5065 C. The use ofpyridine as the solvent is particularly desirable inasmuch as itobviates the need of a thermally vigorous reaction; under theseconditions the reaction is rapid and the crude reaction product is cleanenough to be used in the following step without purification.

The reaction of 4-(4'-methoxyphenoxy)-3-nitrobenzaldehyde with hippuricacid may be carried out in the presence of freshly fused sodium acetate,acetic acid and acetic anhydride on the steam bath. The resultingoxazolone is hydrolyzed with sodium hydroxide. The use of 50% aqueousethanol as solvent for the sodium hydroxide results in a smooth andrapid reaction. The resulting a-benz amido-4- (4'-methoxyphenoxy) 3nitrocinnamic acid is then reduced to the corresponding 3-aminocompound. The reduction may be performed by nascent hydrogen producedfor example with powdered iron. However, catalytic hydrogenation in thepresence of palladium on charcoal catalyst is preferred inasmuch as thereaction mixture is more conveniently worked up following catalytichydrogenation; further, after reduction by the preferred procedure, thereaction mixture may be filtered to remove the catalyst, and useddirectly in the next reaction step without isolation of the reactionproduct. In this manner diazotization of the amine proceeds smoothly.The decomposition of the resulting diazonium compound is carried outwith iodine and an alkali metal iodide such as sodium iodide, andpreferably in the presence of urea. Further, the reaction is bestconducted in a two-phase aqueous solvent system such as chloroform andwater. The product of the above Sandmeyer reaction is regarded as amixture of two substances, namely, a-benzamido-3-iodo-4-(4'-methoxyphenoxy)cinnamic acid and 4-[3-iodo-4-(4'-methoxyphenoxy)benz al]-2-phenyl-5-oxazolone inasmuch asrecrystallization of the crude reaction product has yielded each of thesaid substances. However, each of the latter was found to be readilyconverted to 3-iodothyronine by hydrolysis with a mixture of redphosphorus, hydriodic acid and hydrobromic acid. Accordingly, the crudeproduct resulting from the above Sandmeyer reaction, may be successfullyused, without purification, in the hydrolysis with red phosphorus,hydriodic acid and hydrobromic acid to yield the desired3-iodothyronine.

In the first step of the reaction scheme set forth above, the chlorineatom of 4-chloro-3-nitrobenzaldehyde may be replaced by other halogenatoms, and the methoxy group of 4-methoxyphenol may be replaced by otheralkoxy groups without affecting the feasibility of the entire reactionscheme.

It will be noted that new compounds4-(4'-methoxyphenoxy)-3-nitrobenzaldehyde, 4-[4 (4methoxyphenoxy)-3-nitrobenzal] -2-phenyl-5-oxazolone, a-benzamido-4-(4-methoxyphenoxy)-3-nitrocinnamic acid and ot-benzamido-3-amino-4 (4methoxyphenoxy)cinnamic acid are of value as intermediates in thesynthesis of 3-iodothyronine.

EXAMPLE I (a) 4 (4 '-M ethoxy phenoxy -3-N itrob enzaldehyde To asolution prepared by heating 124 g. (-1 mole) of 4-methoxyphenol, 44.1g. of potassium hydroxide and 125 ml. of pyridine, was added portionwisewith stirring 91.4 g. (0.49 mole) of 4-chloro-3-nitrobenzaldehyde. Thetemperature was maintained at 5055 C. by gentle cooling. After theaddition was complete, the reaction mixture was warmed to 65 C. forabout 5 minutes, cooled and poured onto ice. The resulting oil was takenup in chloroform, washed with water, 4 N hydrochloric acid and water.The solution was dried and evaporated to dryness yielding an oil whichwas used directly in the next step of the reaction scheme. (If desired,the oil can be made to crystallize by cooling and scratching, and the 4resulting crystals are washed with n-propanol and then recrystallizedfrom isopropanol. The pure substance melts at 57.558 C.)

(b) 4- [4-(4'-Methoxyphenoxy)-3-Nitro=benzal] -2- PhenyE-S-Oxazolone Tothe oily product obtained as described in section (a) above, there wasadded 132 g. (0.74 mole) of hippuric acid, 157 g. (1.92 moles) offreshly fused sodium acetate, and 650 ml. of acetic acid. The reactionwas heated on a steam bath with stirring for about 30 minutes and theresulting solution was treated with 650 ml. of acetic auhydride,whereafter heating was continued for 1 hour. The reaction mixture wasthen poured onto 2 liters of ice-water and the resulting precipitate wascollected on a filter and dried. The product weighed 171 g. (84% yieldbased on 4-chloro-3-nitrobenzaldehyde used) and melted at 159-162" C.Recrystallization of the product from aqueous acetic acid raised themelting point to 164- 165 C.

(c) ot-Benzamia0-4-(4-Meth0xyphen0xy)-3-Nitr0- cinnamic Acid Ten grams(0.024 mole) of the oxazolone prepared as described in section (b)above, was mixed with 200 ml. of a 2% solution of sodium hydroxide in50% aqueous ethanol and the mixture was heated under reflux for about 5minutes, whereafter the hot solution was acidified with 20 ml. of 6 Nhydrochloric acid followed by chilling. The resulting precipitate wascollected on a filter, washed with 50% aqueous ethanol and dried. Theresulting product (9.45 g.,- 90% yield) melted at 229-231 C. and wassuitable for use in the next step without further purification.(Recrystallization from ethanol raises the melting point of the productto 231-232" C.)

(d) 4-[3-Iodo-4-(4'-Methoxyphen0ucy)BenzaHM-Phenyl- 5 Ox'azfllone and aBenzamido 3 I0d0-4(4'-Methoxyphenoxy) Cinnamic Acid A solution of 4 g.(0.0092 mole) of the product obtained as described in section (c) above,in 200- ml. of acetic acid was hydrogenated in a Parr hydrogenator inthe presence of 0.5 g. of palladium on charcoal catalyst. The reactionmixture took up the theoretical volume of hydrogen required to reducethe nitro group to the amino group after hydrogenation had proceeded forabout 2 hours. The reaction mixture was then filtered and the filtratewas treated with 90 ml. of Water and 10 ml. of concentrated sulfuricacid. The resulting solution was cooled in an ice bath and treateddropwise with stirring, with a 15% aqueous solution of sodium nitrite,until an excess of nitrite could be detected by means of starch iodidepaper. The theoretical amount of sodium nitrite was usually required.The resulting solution of the diazonium compound was then added to therapidly stirred mixture of ml. of Water, 80 ml. of chloroform, 0.83 g.of urea, 2.5 g. of iodine and 4.4 g. of sodium iodide cooled in an icebath. Stirring and cooling were continued for about 15 minuteswhereafter the temperature was gradually raised to boiling. The mixturewas then allowed to reflux gently for about 30 minutes whereafter thechloroform layer was separated, washed successively with water, 2%aqueous sodium bisulfite and water. The washed solution was dried overmagnesium sulfate and evaporated to dryness leaving 41 g. (87% yield) ofa crude product. This material consisted of a mixture of4-[3-iodo-4-(4'-methoxyphenoxy)benzal]-2- phenyl-S-oxazolone (M.P. 157C.) and or-benzamido-3- riodo-4-(4-methoxyphenoxy)cinuamic acid (M.P.216 0.), either of which was found to be suitable for conversion to 3-iodothyronine in the next step. Accordingly, the crude mixture obtainedabove was suitable for use in the next step without purification.

(e) 3-I0d0thyr0nine To a mixture of 3.8 g. (approximately 0.0076 mole)of the crude product obtained as described in section (d) above 75 ml.of acetic acid and 1.7 g. of red phosphorus, therewas addedwithstirring, 10.7 ml. of a 1:5 mixture by volume of 57% hydriodic acid andacetic acid. The addition was made dropwise while the reaction mixturewas heated under reflux. Refiuxing was maintained for 1 hour whereafter15 ml. of 47% hydrobromic acid was added, and the reaction mixture wasrefluxed for a further hour. The reaction mixture was then filtered hotand the phosphorus retained on the filter was Washed with hot aceticacid. The combined filtrate was cooled to room temperature, neutralizedto about a pH 7 with sodium acetate, and then cooled in an ice-waterbath. The resulting precipitate was collected on a filter and thendissolved in hot 4 N hydrochloric acid. The solution thus obtained wastreated with Norite charcoal, filtered, and the filtrate was cooled. Theprecipitate formed was collected on a filter and dissolved in 3 Naqueous ammonia. The resulting solution was adjusted to pH 9.5 withacetic acid, whereupon a precipitate was formed which was collected anddried. Recrystallization of this product from 50% aqueous acetic acidgave rise to 1.5 g. (49% yield) of the desired 3-iodothyronine meltingat 246- 248 C.

Since certain changes may be made without departing from the scope ofthis invention, it is intended that all matter contained in the abovedescription shall be interpreted as illustrative, and not in a limitingsense.

This application is a division of my (lo-pending application Serial No.646,971, filed March 19, 1957, and now Patent No. 2,954,399.

I claim:

In a method of producing 4-(4'-methoxyphenoxy)-3-nitrobenzaldehyde bythe condensation of 4-chloro-3-nitrobenzaldehyde with 4-methoxyphenol,the improvement which consists of carrying out said condensation in thepresence of potassium hydroxide employing pyridine as the reactionmedium and a reaction temperature between about 50 C. and about C.

References Cited in the file of this patent UNITED STATES PATENTSSchmidt Aug. 27, 1895 Bock et al. Nov. 16, 1954 OTHER REFERENCES

